Abstract
BackgroundHuman cytomegalovirus (HCMV) is known to induce chromosome aberrations in infected cells, which can lead to congenital abnormalities in infected fetuses. HCMV UL76 belongs to a conserved protein family from herpesviruses. Some reported roles among UL76 family members include involvement in virulence determination, lytic replication, reactivation of latent virus, modulation of gene expression, induction of apoptosis, and perturbation of cell cycle progression, as well as potential nuclease activity. Previously, we have shown that stable expression of UL76 inhibits HCMV replication in glioblastoma cells.MethodsTo examine chromosomal integrity and the DNA damage signal γ-H2AX in cells constitutively expressing UL76, immunofluorescent cell staining and Western blotting were performed. The comet assay was employed to assess DNA breaks in cells transiently expressing UL76.ResultsWe report that stably transfected cells expressing UL76 developed chromosome aberrations including micronuclei and misaligned chromosomes, lagging and bridging. In mitotic cells expressing UL76, aberrant spindles were increased compared to control cells. However, cells with supernumerary centrosomes were marginally increased in UL76-expressing cells relative to control cells. We further demonstrated that UL76-expressing cells activated the DNA damage signal γ-H2AX and caused foci formation in nuclei. In addition, the number of cells with DNA breaks increased in proportion to UL76 protein levels.ConclusionOur findings suggest that the virus-associated protein UL76 induces DNA damage and the accumulation of chromosome aberrations.
Highlights
Human cytomegalovirus (HCMV) is known to induce chromosome aberrations in infected cells, which can lead to congenital abnormalities in infected fetuses
Our findings suggest that the virus-associated protein UL76 induces DNA damage and the accumulation of chromosome aberrations
Recent studies have consistently shown that cellular defense mechanisms recognize infections involving a wide range of DNA and RNA viruses as abnormally damaged DNA, including human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), herpes simplex virus (HSV-1), adenovirus, and Simian virus 40 (SV40)
Summary
Human cytomegalovirus (HCMV) is known to induce chromosome aberrations in infected cells, which can lead to congenital abnormalities in infected fetuses. Some reported roles among UL76 family members include involvement in virulence determination, lytic replication, reactivation of latent virus, modulation of gene expression, induction of apoptosis, and perturbation of cell cycle progression, as well as potential nuclease activity. Myriad chromosomal or genomic abnormalities are common in viral lytic and latent infected cells, and even in virus-associated tumors. Cells infected with virus accumulate DNA damage that is directly linked to viral pathogenicity and presumably leads to genomic instability. During life-long infection, the viral life cycle displays multiple phases within the human body. These include active lytic replication, a low level of persistent infection, and insidious latency. Notable clinical complications associated with HCMV infection are in utero congenital infection, opportunistic infection in immunocompromised patients, cardiovascular diseases, and possible malignant tumors [12,13,14,15]
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